Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the invention relates to the use of pyrimidine derivatives for the prophylaxis and therapy of cerebral ischemia.
• R 1 is hydrogen, a C 1 -C 4 -alkyl group, an acetyl or benzoyl group, a phenylalkyl C 1 -C 4 radical, with the aromatic moiety optionally being substituted by halogen, or C 1 -C 4 -alkyl, trifluoromethyl, hydroxyl, C 1 -C 4 -alkoxy, amino, cyano or nitro groups, a naphthylalkyl C 1 -C 3 radical, a phenylalkanone C 2 -C 3 radical or a phenylcarbamoylalkyl C 2 radical, with it being possible for the phenyl group to be substituted by halogen,
• R 2 is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which is optionally monosubstituted, disubstituted or trisubstituted by halogen atoms, C 1 -C 4 -alkyl or trifluoromethyl, trifluoromethoxy, hydroxyl, C 1 -C 4 -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups and which can optionally be fused to a benzene nucleus which can optionally be monosubstituted or disubstituted by halogen atoms, C 1 -C 4 -alkyl or hydroxyl, trifluoromethyl, C 1 -C 4 -alkoxy, amino, cyano or nitro groups and can optionally contain 1 nitrogen atom, or to a 5- or 6-membered ring which can contain 1-2 oxygen atoms, or can be optionally substituted by a
• A is NH or oxygen
• C is hydrogen, methyl or hydroxyl
• Y is CH 2 , CH 2 —CH 2 , CH 2 —CH 2 —CH 2 or CH 2 —CH,
• Z is nitrogen, carbon or CH, with it also being possible for the bond between Y and Z to be a double bond,
• n is the number 2, 3 or 4.
• R 1 has the abovementioned meaning
• R 3 is a cyano group or a C 1-3 -alkyl-carboxylic ester group
• R 4 is C 1-3 -alkyl and C is hydrogen, methyl or hydroxyl, with a primary amine of the formula III
• R 2 and B have the abovementioned meanings, and, where appropriate, converting the resulting compound into the acid addition salt of a physiologically tolerated acid.
• reaction expediently takes place in an inert organic solvent, in particular a lower alcohol, e.g. methanol or ethanol, or a cyclic, saturated ether, in particular tetrahydrofuran or dioxane, or without any solvent.
• a lower alcohol e.g. methanol or ethanol
• a cyclic, saturated ether in particular tetrahydrofuran or dioxane
• the reaction takes place at from 20 to 190° C., in particular from 60 to 90° C., and has generally finished within from 1 to 10 hours.
• R 1 has the abovementioned meanings
• R 3 is a cyano group or a C 1-3 -alkyl-carboxylic ester group
• R 4 is C 1-3 -alkyl and C is hydrogen, methyl or hydroxy, is reacted with a primary amine of the formula IV
• novel compounds of the formula I can be purified either by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or by means of column chromatography.
• the free 3-substituted pyrido[4′,3′:4, 5]thieno[2,3-d]-pyrimidine derivatives of the formula I can be converted, in the customary manner, into the acid addition salts of a solution using the stoichiometric quantity of the corresponding acid.
• pharmaceutically tolerated acids are hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfuric acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
• the trihydrochloride was precipitated, while stirring, by adding ethereal hydrochloric acid, after which the product was filtered off with suction under nitrogen and was rewashed with ethyl acetate. After drying at 50° C. in a vacuum cabinet, 3.6 g (55%) of product having a decomposition point of 282-284° C. were isolated.
• the aqueous phase was reextracted once again with methylene chloride and the combined organic phases were evaporated after having been dried.
• the crude product was purified by column chromatography (silica gel, eluent acetone). This resulted in the isolation of 2.3 g (72%) of product, which was dissolved in 100 ml of ethyl acetate and converted into the hydrochloride, having a m.p. of 233-235° C., using an HCl/ethyl acetate solution.
• the aqueous phase was reextracted once again with methylene chloride and the combined organic phases were evaporated after having been dried.
• the crude product was purified by column chromatography (silica gel, eluent acetone). This resulted in the isolation of 1.0 g (25%) of product, which was dissolved in 100 ml of ethyl acetate and was converted into the hydrochloride, having a m.p. of 190-192° C. (decomp.), using an HCl/ethyl acetate solution.
• These compounds are suitable for treating central nervous system-related emotional disturbances such as seasonal affective disturbances and dysthymia.
• These disturbances also include anxiety states such as generalized anxiety, panic attacks, sociophobia, obsessional neuroses and post-traumatic stress symptoms, disturbances of the memory, including dementia, amnesias and age-related loss of memory, and also psychogenic eating disturbances such as anorexia nervosa and bulimia nervosa.
• R 1 is hydrogen, a C 1 -C 4 -alkyl group, an acetyl group, a phenylalkyl C 1 -C 4 radical, with the aromatic moiety optionally being substituted by halogen, or C 1 -C 4 -alkyl, trifluoromethyl, hydroxyl, C 1 -C 4 -alkoxy, amino, cyano or nitro groups, or a carboxylic-C 1 -C 3 -alkyl ester radical,
• R 2 is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which is optionally monosubstituted or disubstituted by halogen atoms, C 1 -C 4 -alkyl, or trifluoromethyl, trifluoromethoxy, hydroxyl, C 1 -C 4 -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups, and which can optionally be fused to a benzene nucleus which can optionally be monosubstituted or disubstituted by halogen atoms, or C 1 -C 4 -alkyl, hydroxy, trifluoromethyl, C 1 -C 4 -alkoxy, amino, cyano or nitro groups, and which can optionally contain 1 nitrogen atom, or to a 5- or 6-membered ring which can contain 1-2 oxygen atoms,
• A is NH or oxygen
• Y is CH 2 , CH 2 —CH 2 , CH 2 —CH 2 —CH 2 or CH 2 —CH,
• Z is nitrogen, carbon or CH, with it also being possible for the bond between Y and Z to be a double bond,
• n is the number 2, 3 or 4.
• R 1 has the abovementioned meanings
• R 3 is a cyano group or a C 1-3 -alkyl-carboxylic ester group
• R 4 is C 1-3 -alkyl, with a primary amine of the formula III
• R 2 has the abovementioned meanings, and optionally converting the resulting compound into the acid addition salt of a physiologically tolerated acid.
• reaction expediently takes place in an inert organic solvent, in particular a lower alcohol, e.g. methanol or ethanol, or a cyclic, saturated ether, in particular tetrahydrofuran or dioxane.
• a lower alcohol e.g. methanol or ethanol
• a cyclic, saturated ether in particular tetrahydrofuran or dioxane.
• the reaction takes place at from 20 to 110° C., in particular from 60 to 90° C., and has generally finished within from 1 to 10 hours.
• R 1 has the abovementioned meanings
• R 3 is a cyano group or a C 1-3 -alkyl-carboxylic ester group
• R 4 is C 1-3 -alkyl
• novel compounds of the formula I can be purified either by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or by means of column chromatography.
• the free 3-substituted 3,4,5,7-tetrahydropyrrolo[3′,4′:4,5]-thieno[2,3-d]pyrimidine derivatives of the formula I can be converted in the customary manner into the acid addition salts of a solution using the stoichiometric quantity of the corresponding acid.
• pharmaceutically tolerated acids are hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid and citric acid.
• the receptor binding studies were carried out using “membrane preparations” which were obtained from cell cultures of the human embryonic kidney cell line 293 (HEK 293) into which a specific serotonin receptor subtype (h5HT1A, h5HT1B or h5HT1D) has in each case been cloned and in which this subtype is permanently expressed.
• HEK 293 human embryonic kidney cell line 293
• the cells were grown in RPMI 1640 medium (Life Technologies), which additionally contained 10% fetal calf serum (FCS), 2 mmol of L-glutamine/l and 400 mg of geneticin G 418/l .
• FCS fetal calf serum
• the cells were incubated in so-called “tank stacks”, at 37° C. in an incubator gassed with air/5% CO 2 , until they had reached a confluent monolayer.
• the cells were then detached from the culture vessels using a buffer of the following composition: (values per liter) trypsin, 10 mg; EDTA, 4 mg; EGTA, 200 mg; KCl, 200 mg; KH 2 PO 4 , 200 mg; Na 2 HPO 4 , 1.15 g; NaCl, 8.0 g; pH 7.4.
• PBS Dulbecco's phosphate-buffered saline
• novel compounds display a high affinity (K; ⁇ 30 nM) for human 5-HT 1A , 5-HT 1B and 5-HT 1D receptor types, which are expressed in cloned cell lines.
• test substance 50 ⁇ l of the test substance at differing concentrations for competition measurements or 50 ⁇ l of assay buffer or 50 ⁇ l of unlabeled serotonin (1 ⁇ mol/l final volume) for determining the total or non-specific binding control
• radioligand solution [ 3 H]5-carboxamidotryptamine (5-CT) for the h5HT1B and h5RT1D receptors or [ 3 H]8-hydroxydipropylaminotetralin (8-OH-DPAT) for the h5HT1A receptors.
• the final concentrations of the radioligands were adjusted to 3 nmol/l or 0.3 nmol/l.
• the assay mixture was incubated at 25° C. for 30 min and then filtered through a fiberglass filter (Whatman GF/B) using a cell harvesting appliance (Skatron), with the filters then being washed with from 5 to 9 ml of cold buffer.
• the filters were in each case placed, together with 5 ml of Ultima GoldxR liquid scintillator (Packard), in scintillation vials, which were shaken for 1 hour.
• the radioactivity was then determined in a beta counter (Wallac).
• the measurement data were evaluated by an iterative non-linear regression analysis using the “Statistical Analysis System (SAS)” which is similar-to the “LIGAND” program described by Munson and Rodbard (Anal. Biochem: 107, 220 (1980)).
• the competition constants (K i ) were recorded in nmol/l.
• These compounds are suitable for treating central nervous system-related emotional disturbances such as seasonal affective disturbances and dysthymia.
• These disturbances also include anxiety states such as generalized anxiety, panic attacks, sociophobia, obsessional neuroses and post-traumatic stress symptoms, disturbances of the memory, including dementia, amnesias and age-related loss of memory, and also psychogenic eating disturbances such as anorexia nervosa and bulimia nervosa.
• R 1 and R 2 are hydrogen or a C 1 -C 4 -alkyl group
• R 3 is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which is optionally monosubstituted or disubstituted by halogen atoms, C 1 -C 4 -alkyl, or trifluoromethylt trifluoromethoxy, hydroxy, C 1 -C 4 -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups, and which can optionally be fused to a benzene nucleus which can optionally be monosubstituted or disubstituted by halogen atoms, or C 1 -C 4 -alkyl, hydroxy, trifluoromethyl, C 1 -C 4 -alkoxy, amino, cyano or nitro groups and which can optionally contain 1 nitrogen atom, or to a 5- or 6 -membered ring which can contain 1-2 oxygen atoms,
• A is NH or oxygen
• Y is CH 2 , CH 2 —CH 2 , CH 2 —CH 2 —CH 2 or CH 2 —CH,
• Z is nitrogen, carbon or CH, with it also being possible for the bond between Y and Z to be a double bond,
• n is the number 2, 3 or 4.
• R 1 has the abovementioned meanings
• R 3 is a cyano group or a C 1-3 -alkyl-carboxylic ester group
• R 4 is C 1-3 -alkyl, with a primary amine of the formula III
• R 3 has the abovementioned meanings, and optionally converting the resulting compound into the acid addition salt of a physiologically tolerated acid.
• reaction expediently takes place in an inert organic solvent, in particular a lower alcohol, e.g. methanol or ethanol, or a cyclic, saturated ether, in particular tetrahydrofuran or dioxane.
• a lower alcohol e.g. methanol or ethanol
• a cyclic, saturated ether in particular tetrahydrofuran or dioxane.
• the reaction takes place at from 20 to 110° C., in particular at from 60 to 90° C., and has generally finished within from 1 to 10 hours.
• R 1 has the abovementioned meaning
• R 3 is a cyano group or a C 1-3 -alkyl-carboxylic ester group
• R 4 is C 1-3 -alkyl
• novel compounds of the formula I can be purified either by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or by means of column chromatography.
• the free 3-substituted pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidine derivatives of the formula I can be converted, in the customary manner, into the acid addition salts of a solution using the stoichiometric quantity of the corresponding acid.
• pharmaceutically tolerated acids are hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfuric acid, maleic acid, fumaric acid, oxalic acid, tartaric acid and citric acid.
• These compounds are suitable for treating central nervous system-related emotional disturbances such as seasonal affective disturbances and dysthymia.
• These disturbances also include anxiety states such as generalized anxiety, panic attacks, sociophobia, obsessional neuroses and post-traumatic stress symptoms, disturbances of the memory, including dementia, amnesias and age-related loss of memory, and also psychogenic eating disturbances such as anorexia nervosa and bulimia nervosa.
• R 1 is hydrogen, a C 1 -C 4 -alkyl group, an acetyl group, a phenylalkyl C 1 -C 4 radical, with the aromatic moiety optionally being substituted by halogen or C 1 -C 4 -alkyl, trifluoromethyl, hydroxyl, C 1 -C 4 -alkoxy, amino, cyano or nitro groups, or a phenylalkanone radical, with it being possible for the phenyl group to be substituted by halogen,
• R 2 is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which is optionally monosubstituted or disubstituted by halogen atoms, C 1 -C 4 -alkyl or trifluoromethyl, trifluoromethoxy, hydroxyl, C 1 -C 4 -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups and which can be optionally fused to a benzene nucleus which can be optionally monosubstituted or disubstituted by halogen atoms or C 1 -C 4 -alkyl, hydroxyl, trifluoromethyl, C 1 -C 4 -alkoxy, amino, cyano or nitro groups and can optionally contain 1 nitrogen atom, or to a 5- or 6-membered ring which can contain 1-2 oxygen atoms,
• A is NH or oxygen
• Y is CH 2 , CH 2 —CH 2 , CH 2 —CH 2 —CH 2 or CH 2 —CH,
• Z is nitrogen, carbon or CH, with it also being possible for the bond between Y and Z to be a double bond,
• n is the number 2, 3 or 4.
• R 1 has the abovementioned meanings
• R 3 is a cyano group or a C 1-3 -alkyl-carboxylic ester group
• R 4 is C 1-3 -alkyl, with a primary amine of the formula III
• R 2 has the abovementioned meanings, and, where appropriate, converting the resulting compound into the acid addition salt of a physiologically tolerated acid.
• reaction expediently takes place in an inert organic solvent, in particular a lower alcohol, e.g. methanol or ethanol, or a cyclic, saturated ether, in particular tetrahydrofuran or dioxane.
• a lower alcohol e.g. methanol or ethanol
• a cyclic, saturated ether in particular tetrahydrofuran or dioxane.
• the reaction takes place at from 20 to 110° C., in particular from 60 to 90° C., and has generally finished within from 1 to 10 hours.
• R 1 has the abovementioned meanings
• R 3 is a cyano group or a C 1-3 -alkyl-carboxylic ester group
• R 4 is C 1-3 -alkyl
• novel compounds of the formula I can either be purified by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or by means of column chromatography.
• the free 3-substituted pyrido[3′,4′:4,5]thieno[2,3-d]-pyrimidine derivatives of the formula I can be converted, in the customary manner, into the acid addition salts of a solution using the stoichiometric quantity of the corresponding acid.
• pharmaceutically tolerated acids are hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfuric acid, maleic acid, fumaric acid, oxalic acid, tartaric acid and citric acid.
• the 5-acetyl derivatives were prepared from 1-acetyl-3-piperidone in analogy with a) and b) (P. Krogsgaard-Larsen, H. Hjeds: Acta Chem. Scand B 30, 884 (1976)).
• the acetyl group in the 6 position can, in analogy with DE 19 636 769.7, be eliminated with 10 percent hydrochloric acid, while boiling under reflux, to give the corresponding secondary amines.
• the alkylations at N-6 to give the 6-alkyl derivatives can likewise be performed as described in DE 19 636 769.7.
• These compounds are suitable for treating central nervous system-related emotional disturbances such as seasonal affective disturbances and dysthymia.
• These disturbances also include anxiety states such as generalized anxiety, panic attacks, sociophobia, obsessional neuroses and post-traumatic stress symptoms, disturbances of the memory, including dementia, amnesias and age-related loss of memory, and also psychogenic eating disturbances such as anorexia nervosa and bulimia nervosa.
• A is NH or oxygen
• C is hydrogen, methyl or hydroxyl
• D and E are together —CH 2 —CH 2 —NR 1 —CH 2 —, —CH 2 —NR 1 —CH 2 — or —CH 2 —NR 1 —CH 2 —CH 2 —,
• Y is CH 2 , CH 2 —CH 2 , CH 2 —CH 2 —CH 2 or CH 2 —CH,
• Z is nitrogen, carbon or CH, with it also being possible for the bond between Y and Z to be a double bond,
• n is the number 2, 3 or 4,
• R 1 is hydrogen, a C 1 -C 4 -alkyl group, an acetyl or benzoyl group, a phenylalkyl C 1 -C 4 radical or phenylalkoxy C 2 -C 5 radical, with the aromatic moiety optionally being substituted by halogen, or C 1 -C 4 -alkyl, trifluoromethyl, hydroxyl, C 1 -C 4 -alkoxy, amino, cyano or nitro groups, a naphthylalkyl C 1 -C 3 radical, a phenylalkanone C 2 -C 4 radical or a phenyl- or pyridylcarbamoylalkyl C 2 radical, with it being possible for the phenyl or pyridyl group to be substituted by halogen, a C 1 -C 3 -alkyl group, a methoxy group and by a nitro or amino group,
• R 2 is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which is optionally monosubstituted, disubstituted or trisubstituted by halogen atoms, C 1 -C 4 -alkyl or trifluoromethyl, trifluoromethoxy, hydroxyl, C 1 -C 4 -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups and which can optionally be fused to a benzene nucleus which can optionally be monosubstituted or disubstituted by halogen atoms, C 1 -C 4 -alkyl or hydroxyl, trifluoromethyl, C 1 -C 4 -alkoxy, amino, cyano or nitro groups and which can optionally contain 1 nitrogen atom, or to a 5- or 6-membered ring which can contain 1-2 oxygen atoms, or can be substituted by a
• R 3 and R 4 are, independently of each other, hydrogen or a C 1 -C 4 -alkyl group
• a use according to the invention also concerns neuroprotection.
• a medicament is produced using a compound of the formula I, or its pharmacologically tolerated acid addition salt, as the active compound, together with customary excipients and diluents.
• the use according to the invention can be effected, in the customary manner, orally or parenterally, intravenously or intramuscularly.
• the daily dose of active compound depends on the age, condition and weight of the patient and on the type of administration.
• the daily dose of active compound is from about 1 to 100 mg/kg of body weight in the case of oral administration and from 0.1 to 10 mg/kg of body weight in the case of parenteral administration.
• the medicaments can be used in the usual pharmaceutical administration forms in the solid or liquid state, e.g. as tablets, film tablets, capsules, powders, granules, coated tablets, suppositories, solutions, ointments, creams or sprays. These forms are produced in the customary manner.
• the active compounds can be worked up with the customary pharmaceutical auxiliary substances such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, crosslinking agents, dispersants, emulsifiers, solvents, delayed release agents, antioxidants and/or propellant gases (cf. H. Sucker et. al: Pharmazeutician Technologie (Pharmaceutical Technology), Thieme-Verlag, Stuttgart, 1978).
• the resulting administration forms normally comprise the active compound in a quantity of from 1 to 99% by weight.

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• 1999
  • 1999-01-11 DE DE19900545A patent/DE19900545A1/de not_active Withdrawn
  • 1999-12-22 CZ CZ20012484A patent/CZ20012484A3/cs unknown
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  • 1999-12-24 CZ CZ20012485A patent/CZ20012485A3/cs unknown
  • 1999-12-24 KR KR1020017008692A patent/KR20010101442A/ko not_active Application Discontinuation
  • 1999-12-24 PL PL99348920A patent/PL348920A1/xx not_active Application Discontinuation
  • 1999-12-24 MX MXPA01006967A patent/MXPA01006967A/es not_active Application Discontinuation
  • 1999-12-24 EP EP99967980A patent/EP1140096A1/de not_active Withdrawn
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  • 1999-12-24 WO PCT/EP1999/010369 patent/WO2000041695A1/de not_active Application Discontinuation
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